The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
CLEVER-1 is a protein disclosed in WO 03/057130, Common Lymphatic Endothelial and Vascular Endothelial Receptor-1. It is a binding protein that mediates adhesion of lymphocytes (and malignant tumor cells) to endothelium in both the systemic vasculature and in the lymphatics. By blocking the interaction of Clever-1 and its lymphocyte substrate it is possible to simultaneously control lymphocyte recirculation and lymphocyte migration, and related conditions such as inflammation, at the site of lymphocyte influx into, and efflux from, the tissues. WO 03/057130 also discloses that Clever-1 mediates binding of other types of leukocytes such as monocytes and granulocytes to HEV-like vessels. Thus, by blocking the interaction of Clever-1 and malignant tumor cells it became possible to control metastasis by preventing malignant cells that bind to Clever-1 from being taken up by the lymphatic vessels, and thus to prevent spread of the malignancy into the lymph nodes.
Clever-1 is expressed in lymphatic endothelial cells, certain vascular endothelial cells, but also in a subpopulation of macrophages. On macrophages Clever-1 is known to function as a scavenging receptor, which can mediate endocytic uptake of various molecules such as oxidized-LDL.
Macrophages are traditionally divided into type 1 and type 2 cells. Type 1 macrophages are classical proinflammatory macrophages, which produce large quantities of proinflammatory cytokines and co-stimulatory molecules, and are very efficient in activation of T-cell responses. Type 2 macrophages, in contrast, are immune suppressing cells, which synthesize anti-inflammatory cytokines and induce regulatory T cells and hence profoundly dampen antigen-driven T cell activation. Tumor-associated macrophages are considered harmful as they mature to type 2 macrophages within the tumor environment and suppress anti-tumor immune response (Martinez, F. O. et al. Macrophage activation and polarization. Front. Biosci. 13:453-461.) and mediate angiogenic switch, a crucial step in cancer growth (Lin, E. Y., and Pollard, J. W. 2007. Tumor-associated macrophages press the angiogenic switch in breast cancer. Cancer Res. 67:5064-5066).
Pregnancy poses a challenge to the immune system, since half of the fetal antigens comes from the paternal origin, which is foreign to the mother. Several immune suppressing mechanisms are known to operate in the placenta to prevent the rejection of the fetus, which can be regarded as a semi-allograft for the maternal immune system. Among the best known examples are expression of non-classical MHC molecules, inhibition of the NK-cell activity, induction of T regulatory cell activity, induction T cell apoptosis and inhibition of complement activation. The suppression of antigen presenting cell activity can also contribute to the induction of tolerance. Among the antigen presenting cells macrophages are prominently present in the placenta.